Epothilones are macrolide compounds having utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
may be found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL®) and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Hofle et al., Angew. Chem. Int. Ed. Engl., Vol. 35, No. 13/14, 1567–1569 (1996); WO 93/10121 published May 27, 1993; and WO 97/19086 published May 29, 1997.
Derivatives and analogs of Epothilones A and B have been synthesized and may be used to treat a variety of cancers and other abnormal proliferative diseases. Such analogs are disclosed in Hofle et al., Id.; Nicolaou et al., Angew Chem. Int. Ed. Engl., Vol. 36, No. 19, 2097–2103 (1997); and Su et al., Angew Chem. Int. Ed. Engl., Vol. 36, No. 19, 2093–2097 (1997).
Analogs of the epothilones that have been found to have advantageous activity are represented by formula I:
wherein the various symbols are as defined below. While these compounds possess significant therapeutic properties, they also present difficulties to those skilled in the art of pharmaceutical compounding, as a result of certain properties, as will be detailed hereinbelow. In accordance with the present invention, a formulation has been found whereby the epothilone analogs described above can be safely dispensed and administered via injection, without appreciable loss of potency.